SNAP-tag and CLIP-tag are both derived from O6 -alkylguanine-DNA-alkyltransferase (hAGT). SNAP-tag recognizes O6-labeled benzylguanine substrates while CLIP-tag recognizes O2-labeled benzylcytosine substrates. Each tag transfers the label from the substrate to itself, resulting in specific covalent labeling. In creating the tags, hAGT has been engineered to no longer interact with DNA, but rather with derivatives of the free benzylguanine or benzylcytosine substrates. The tags exhibit no cross-reactivity with one another, enabling researchers to simultaneously label fusion proteins containing SNAP- and CLIP-tags with different fluorophores in live cells.